Identifying neurons for interoception using simultaneous profiling of activity- and projection- specific populations

使用活动和投射特定群体的同步分析来识别用于内感受的神经元

• 批准号: 10687590
• 负责人: Sarah Stern
• 金额: $ 169.98万
• 依托单位: MAX PLANCK FLORIDA CORPORATION
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10687590
• 关键词: Addictive Behavior; Affinity Chromatography; Animal Model; Anorexia; Anterior; Area; Back; Behavior; Behavior Disorders; Behavioral; Brain; Brain region; Communities; Complex; Detection; Eating Disorders; Functional disorder; Genes; Homeostasis; Interoception; Link; Maps; Mental disorders; Methodology; Methods; Modality; Molecular Profiling; Neurons; Neurosciences; Patient Self-Report; Physiological; Population; Process; Ribosomes; Role; Techniques; Tissues; Translating; Validation; addiction; bodily sensation; body sense; cell type; experimental study; human imaging; imaging study; insight; maladaptive behavior; molecular marker; neural; neural circuit; next generation; non-verbal; novel; single-cell RNA sequencing; transcriptome sequencing; transcriptomics

Project Summary Interoception, the process by which the body senses its own internal state, is critical to maintaining homeostasis through the detection of physiological changes that enable the body to adjust to changing demands. Dysfunction in interoception may lead to erroneous prediction errors concerning these bodily needs and is increasingly considered to underlie a number of maladaptive behaviors and psychiatric disorders, including addiction and eating disorders. Despite this, little progress has been made in identifying the underlying neural circuit mechanisms of interoception because non-verbal subjects (e.g. animal models) cannot self-report internal states. Here, we propose a novel conceptual behavioral framework for studying interoception in animal models in order to identify neuronal ensembles that encode interoception. Moreover, human imaging studies have informed us that interoception relies critically on an understudied area of the brain, the insular cortex, but the functions and corresponding projections from the insular cortex subregions (anterior to posterior) have not been well-studied. Methods that can simultaneously deliver precise information concerning behavior and projections in a high-throughput way are therefore required. Molecular profiling techniques have been increasingly useful for identifying cell types that might serves as the link between genes to circuits, but current techniques have limitations, namely the modality by which the profiling occurs. We therefore also propose a new transcriptomic molecular profiling technique, called SNAP-TRAP (Simultaneous Neuronal Activity and Projection – Translating Ribosome Affinity Purification), that enables coincident profiling of both activity-dependent and projection-specific neuronal markers. We will validate this technique using a well-defined neural circuit with known molecular markers and behavioral consequences. We will then apply the methodology to the insular cortex and its role in interoception. This technique will also enable us to make comparisons of next-generation RNA-sequencing to single- cell RNA sequencing for the purpose of identifying useful markers for behavioral validation. Lastly, we will map our findings back onto tissue sections to achieve spatial transcriptomic information. Through these experiments we hope to achieve a comprehensive transcriptomic map of the insular cortex that can be precisely delineated according to particular behaviors and projections, and can be used as a basis for understanding how dysfunction in interoception leads to maladaptive behaviors. The SNAP- TRAP technique may then be used by the broader neuroscience community in other brain regions and behavioral tasks to gain insights into the neural underpinnings of complex behaviors and their associated psychiatric disorders.

项目摘要 拦截，即身体感觉自己内在状态的过程，对于维持 通过检测身体变化，使身体适应变化，体内稳态 需求。互认为功能障碍可能导致有关这些身体的错误 需求并越来越被认为是许多不良适应行为和精神病的基础 疾病，包括成瘾和饮食失调。尽管如此，几乎没有进展 识别拦截的潜在神经回路机制，因为非语言受试者（例如 动物模型）不能自我报告内部状态。在这里，我们提出了一种新颖的概念行为 研究动物模型中研究的框架，以识别神经元合奏 编码拦截。此外，人类成像研究告诉我们，拦截依赖于 批判性的大脑区域，即岛状皮质，但功能和相应的功能 从岛状皮层子区域（后部前）的投影尚未得到充分研究。 可以轻松传递有关行为和项目的精确信息的方法 因此，需要高通量方式。分子分析技术已经增加 对于识别可能用作基因与电路之间链接的细胞类型有用，但是当前 技术有局限性，即分析发生的方式。因此，我们也是如此 提案一种新的转录组分子分析技术，称为snap-trap（同时） 神经元活动和投影 - 翻译核糖体亲和力纯化），使得能够重合 活动依赖性和投影特异性神经元标记物的分析。我们将验证这个 使用具有已知分子标记和行为的明确的神经回路的技术 结果。然后，我们将将方法应用于岛状皮质及其在互认为中的作用。 这项技术还将使我们能够比较下一代RNA的测序 细胞RNA测序是为了确定行为验证的有用标记。最后，我们 将我们的发现映射回组织部分以获得空间转录组信息。通过 这些实验我们希望获得一张综合的岛状皮质的转录组图 可以根据特定的行为和项目精确地描述，可以用作 理解拦截中功能障碍如何导致适应不良行为的基础。快照 - 然后，陷阱技术可以由其他大脑区域的更广泛的神经科学界使用， 行为任务以了解复杂行为及其的神经基础的见解 相关的精神疾病。